Schizophrenia pathology has long been associated with stress and/or immunity, although their etiological paths to the disease are far from clear. The kynurenine pathway of tryptophan degradation is a strong candidate for the missing link because enzymes that gate the first step of the conversion of tryptophan to kynurenine are influenced by stress, glucocorticoids and the immune system. However, the downstream mechanisms connecting increased kynurenine synthesis and pathological events in schizophrenia involve multiple chemical changes, which are not necessarily identical in the periphery and in the brain. In other words, in spite of the attractiveness and plausibility of the hypothetical link between kynurenine pathway metabolism and schizophrenia, and especially the presumed prominent etiological role of the pathway metabolite kynurenic acid, the field lacks a coherent explanatory model, hindering meaningful pre-clinical- clinical translations. The difficulty may be due to the inherent complexity of the system and its interactions with other systems, but also to the lack of a comprehensive clinical effort to understand the connection between the kynurenine pathway and the core features of schizophrenia patients. The present effort is designed to change that by examining the impact of stress and cytokine mechanisms on kynurenine pathway metabolites in schizophrenia patients, and by evaluating the relevance of these new findings to pathophysiology. Based on the strong pre-clinical evidence for causality and embracing the complexity of the system, the project is designed to test the trajectory from stress/cytokines to kynurenine pathway metabolites to clinical and brain abnormalities in schizophrenia using an array of state-of-the-art imaging, electrophysiology, and modeling approaches. This study will therefore comprehensively investigate the extent of the involvement of the kynurenine pathway in mediating the effects of stress and immune function on core clinical and biological abnormalities in schizophrenia, and define the key biomarkers associated with the kynurenine pathway in schizophrenia. This new knowledge regarding the involvement of kynurenine pathway metabolism in schizophrenia patients will lead to more specific and better treatment targets for drug development.